Aripiprazole complex formulation and method

ABSTRACT

An aripiprazole formulation is provided which includes the antipsychotic agent aripiprazole in the form of an inclusion complex in a β-cyclodextrin, preferably, sulfobutyl ether β-cyclodextrin (SBECD), which in the form of an injectable produces reversible generally minimal to mild irritation at the intramuscular injection site. A method for minimizing or reducing irritation caused by aripiprazole at an intramuscular injection site and a method for treating schizophrenia employing the above formulation are also provided.

FIELD OF THE INVENTION

[0001] The present invention relates to an aripiprazole inclusioncomplex with a substituted β-cyclodextrin, an aripiprazole formulationwhich includes aripiprazole in the form of the above inclusion complex,an injectable formulation which contains the above complex ofaripiprazole, a method for reducing irritation normally caused byaripiprazole at an intramuscular injection site employing the aboveinjectable formulation and a method for treating schizophrenia employingthe above formulation.

BACKGROUND OF THE INVENTION

[0002] U.S. Pat. No. 5,006,528 to Oshiro et al. discloses7-[(4-phenylpiperazino)-butoxy] carbostyrils, which includearipiprazole, as dopaminergic neurotransmitter antagonists.

[0003] Aripiprazole which has the structure

[0004] is an atypical antipsychotic agent useful in treatingschizophrenia. It has poor aqueous solubility (<1 μg/mL at roomtemperature). When formulated as an intramuscular (IM) injectablesolution, aripiprazole has been found to cause unacceptable (moderate tosevere) tissue irritation at the muscular site with many water-miscibleco-solvent systems, and water-immiscible solvent and co-solvent systemssuch as hexonoic acid: medium chain triglyceride (10:90), polyethyleneglycol 400:ethanol:lactic acid (35:15:50), benzyl alcohol:sesame oil(10:90), benzyl alcohol:medium chain triglyceride (10:90), benzylalcohol:tributyrin (5:95), and polysorbate 80 in 25 mM tartaric acid.

[0005] Cyclodextrins are known for their use in increasing solubility ofdrugs. They function by forming inclusion complexes with hydrophobicmolecules. Unfortunately, there are many drugs for which cyclodextrincomplexation either is not possible or produces no apparent advantagesas disclosed by J. Szejtli, Cyclodextrins in Drug Formulations:Part II,Pharmaceutical Technology, 24-38, August, 1991.

[0006] U.S. Pat. Nos. 5,134,127 and 5,376,645 each to Stella et al.disclose sulfoalkyl ether cyclodextrin derivatives and their use assolubilizing agents for water-insoluble drugs for oral, intranasal orparenteral administration including intravenous and intramuscular.Stella et al. disclose an inclusion complex of the water-insoluble drugand the sulfoalkyl ether cyclodextrin derivative and pharmaceuticalcompositions containing same. Examples of sulfoalkyl ether cyclodextrinderivatives disclosed include mono-sulfobutyl ether of β-cyclodextrinand monosulfopropyl ether of β-cyclodextrin. Examples of water-insolubledrugs are set out in column 7 starting at line 25 and include, amongothers, benzodiazepines, chlorpromazine, diazepam, mephorbarbital,methbarbital, nitrazepam, and phenobarbital.

[0007] U.S. Pat. No. 6,232,304 to Kim et al. discloses inclusioncomplexes of aryl-heterocyclic salts such as the tartrate salt ofziprasidone in a cyclodextrin such as β-cyclodextrin sulfobutyl ether(SBECD), and hydroxypropyl-β-cyclodextrin (HPBCD), and use of suchinclusion complexes in oral and parenteral formulations.

[0008] Japanese Patent Application No. 09301867A2 dated Nov. 25, 1997discloses antidepressant compositions in the form of tablets containingaripiprazole.

[0009] EP1145711A1 dated Oct. 17, 2001 (based on U.S. application Ser.No. 2000-547948 filed Apr. 12, 2000) discloses flash-melt oral dosageformulations containing aripiprazole.

[0010] U.S. Pat. No. 5,904,929 to Uekama et al. discloses trans-mucosaland transdermal pharmaceutical compositions containing a drug and aperacylated cyclodextrin as a solubilizing agent. Examples of drugsinclude antidepressants such as amitriptyline HCl, amoxapine,butriptyline HCl, clomipramine HCl, desipramine HCl, dothiepin HCl,doxepin HCl, fluoxetine, gepirone, imipramine, lithium carbonate,mianserin HCl, milnacipran, nortriptyline HCl and paroxetine HCl;anti-muscarinic agents such as atropine sulphate and hyoscine; sedatingagents such as alprazolam, buspirone HCl, chlordiazepoxide HCl,chlorpromazine, clozapine, diazepam, flupenthixol HCl, fluphenazine,flurazepam, lorazepam, mazapertine, olanzapine, oxazepam, pimozide,pipamperone, piracetam, promazine, risperidone, selfotel, seroquel,sulpiride, temazepam, thiothixene, triazolam, trifluperidol andziprasidone; anti-migraine drugs such as alniditan and sumatriptan;beta-adrenoreptor blocking agents such as atenolol, carvedilol,metoprolol, nebivolol and propranolol; anti-Parkinsonian drugs such asbromocryptine mesylate, levodopa and selegiline HCl; opioid analgesicssuch as buprenorphine HCl, codeine, dextromoramide and dihydrocodeine;parasympathomimetics such as galanthamine, neostigmine, physostymine,tacrine, donepezil, ENA 713 (exelon) and xanomeline; and vasodilatorssuch as amlodipine, buflomedil, amyl nitrite, diltiazem, dipyridamole,glyceryl trinitrate, isosorbide dinitrate, lidoflazine, molsidomine,nicardipine, nifedipine, oxpentifylline and pentaerythritoltetranitrate.

BRIEF DESCRIPTION OF THE INVENTION

[0011] In accordance with the present invention, there is provided aninclusion complex of aripiprazole in a substituted-beta-cyclodextrin. Ithas been found that the inclusion complex of aripiprazole issubstantially more water-soluble relative to the non-complexedaripiprazole.

[0012] Surprisingly and unexpectedly, it has been found that whenaripiprazole is complexed with a substituted β-cyclodextrin such assulfobutyl ether-β-cyclodextrin, it may be formulated as an injectablewhich delivers aripiprazole to the muscular site with unexpectedlydiminished irritation as compared to injectables containing uncomplexedaripiprazole.

[0013] In addition, in accordance with the present invention, apharmaceutical formulation is provided which is formed of an inclusioncomplex of aripiprazole and a substituted-β-cyclodextrin, and apharmaceutically acceptable carrier therefor.

[0014] In a preferred embodiment, the pharmaceutical formulation of theinvention will be in the form of an aqueous parenteral or injectableformulation. However, the pharmaceutical formulation of the inventionmay be in other dosage forms such as lyophilized injectable, oral (forexample tablets, capsules, elixirs and the like), transdermal ortransmucosal forms or inhalation forms.

[0015] Further, in accordance with the present invention, a method isprovided for administering injectable aripiprazole without causingunacceptable irritation at the site of injection wherein the abovedescribed injectable formulation is administered, preferablyintramuscularly, to a patient in need of treatment.

[0016] Still further in accordance with the present invention, a methodis provided for treating schizophrenia which includes the step ofadministering to a patient in need of treatment the above describedformulation, preferably in injectable form, without causing undueirritation at the site of injection, whether it be at a muscular site orother site.

DETAILED DESCRIPTION OF THE INVENTION

[0017] Aripiprazole has poor water solubility and thus is difficult toformulate as an aqueous injectable. In accordance with the presentinvention, it as been found that the water-solubility of aripiprazolemay be sufficiently increased to allow it to be formulated as an aqueousinjectable by complexing aripiprazole with a substituted-β-cyclodextrin.In effect, the cyclodextrin inhibits precipitation of the aripiprazoleat the site of injection. The aqueous injectable formulation containingthe complex of aripiprazole and the substituted-β-cyclodextrin may beadministered preferably intramuscularly without causing unacceptableirritation at the muscular site. This is indeed surprising andunexpected since, as indicated above, a host of water-miscibleco-solvent systems and water-immiscible co-solvent systems have beenfound to be unacceptable as carriers for injectable aripiprazoleformulations because of the unacceptable irritation profile of suchformulations. On the other hand, the aqueous injectable formulation ofthe invention delivers aripiprazole without causing unacceptableirritation at the site of injection.

[0018] As will be seen hereinafter, the aripiprazole formulation in theform of an aqueous injectable will include an acid buffer and a base toadjust pH to desired levels.

[0019] The substituted-β-cyclodextrin suitable for use herein refers tosulfobutyl ether β-cyclodextrin (SBECD) and hydroxypropyl-β-cyclodextrin(HPBCD), with SBECD being preferred.

[0020] The term “undue irritation” or “unacceptable irritation” at thesite of injection or at the muscular site refers to moderate to severeirritation which is unacceptable to the patient and thereby impactsunfavorably on patient compliance.

[0021] The term “reduced irritation” at the site of injection or at themuscular site refers to generally minimal to mild irritation which isacceptable to the patient and does not impact unfavorably on patientcompliance.

[0022] The aripiprazole will form a complex with thesubstituted-β-cyclodextrin which complex may be dissolved in water toform an injectable formulation. However, physical mixtures ofaripiprazole and the substituted-β-cyclodextrin are within the scope ofthe present invention as well.

[0023] The complex or the physical mixture may also be compressed into atablet or may be filled into capsules.

[0024] The aripiprazole formulations of the invention may be formed ofdry physical mixtures of aripiprazole and the substituted-β-cyclodextrinor dry inclusion complexes thereof which upon addition of water arereconstituted to form an aqueous injectable formulation. Alternatively,the aqueous injectable formulation may be freeze dried and laterreconstituted with water. Thus, the inclusion complex in accordance withthe invention, may be pre-formed, formed in situ or formed in vivo (inthe gastrointestional tract or the buccal cavity). All of the above arecontemplated by the present invention.

[0025] The aripiprazole formulation of the invention in the form of anaqueous injectable will include an acid buffer to adjust pH of theaqueous injection within the range from about 3.5 to about 5. Examplesof acid buffers suitable for use herein include acids such ashydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid andthe like, and organic acids such as oxalic acid, maleic acid, fumaricacid, lactic acid, malic acid, tartaric acid, citric acid, benzoic acid,acetic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonicacid, ethanesulfonic acid and the like. Acid salts of the above acidsmay be employed as well. Preferred acids are tartaric acid, citric acid,and hydrochloric acid. Most preferred is tartaric acid.

[0026] The injectable formulation of the invention will have a pH withinthe range from about 3.5 to about 5, preferably from about 4 to about4.6, and most preferably about 4.3. In formulating the injectable, ifnecessary, the pH may be adjusted with a base such as an alkali metalhydroxide such as NaOH, KOH, or LiOH, preferably NaOH, or an alkalineearth metal hydroxide, such as Mg(OH)₂ or Ca(OH)₂.

[0027] In preparing the aqueous injectable formulation of the invention,the substituted-β-cyclodextrin will be employed in a weight ratio to thearipiprazole within the range from about 5:1 to 400:1, preferably fromabout 10:1 to about 100:1. Each type of cyclodextrin employed requires adifferent ratio to inhibit or prevent precipitation of aripiprazole atthe injection site. In preferred embodiments of the aqueous injectableof the invention, the substituted-β-cyclodextrin will be SBECD whichwill be employed in a weight ratio to aripiprazole within the range fromabout 5:1 to about 400:1, preferably from about 20:1 to about 40:1. Thecyclodextrin may be present in an amount greater than that needed tocomplex the aripiprazole since the additional cyclodextrin could aid indissolution of the aripiprazole.

[0028] The aripiprazole will be present in the aqueous injectableformulation in an amount within the range from about 0.1 to about 2.5%by weight, preferably from about 0.2 to about 1.5% by weight based onthe total injectable formulation.

[0029] In preferred embodiments, the aripiprazole will be present in theaqueous injectable formulation to provide from about 1 to about 20 mg/mLof formulation, preferably from about 1.5 to about 8 mg/ML offormulation.

[0030] In more preferred embodiments, the formulations of the inventionwill provide 2 mg aripiprazole/mL, 5 mg/mL and 7.5 mg/mL. Fill volumeswill preferably be 0.5 mL and 2 mL.

[0031] A preferred injectable formulation is as follows:

[0032] (1) aripiprazole—in an amount to provide from about 1.5 to about8 mg/mL of solution.

[0033] (2) SBECD—in an amount from about 100 to about 200 mg/mL ofsolution.

[0034] (3) acid buffer (preferably tartaric acid)—in an amount fromabout 7 to about 9 mg/mL of solution to adjust pH from about 3.5 toabout 5.

[0035] (4) base to adjust pH, preferably an alkali metal hydroxide,preferably NaOH—in an amount to adjust pH from about 4 to 4.6

[0036] (5) water qs to 1 mL.

[0037] The aripiprazole injectable formulation of the invention may beprepared as follows: Tartaric acid or other acid buffer is dissolved inwater for injection. The substituted-β-cyclodextrin (preferably SBECD)is dissolved in the acid buffer-water solution. Aripiprazole is thendissolved in the solution. The pH of the solution is adjusted to withinthe range from about 3.5 to about 5, preferably about 4.3 by addingbase, such as sodium hydroxide or other alkali metal hydroxide oralkaline earth metal hydroxide. Additional water for injection is addedto obtain the desired batch volume.

[0038] The resulting solution is aseptically filtered, for example,through a 0.22μ membrane filter and filled into vials. The vials arestopped and sealed and terminally sterilized.

[0039] The aqueous injectable formulation of the invention will providean amount of aripiprazole of at least 2 mg aripiprazole/mL, preferablyat least 5 mg aripiprazole/mL, when the amount of aripiprazole providedby the complex is measured at a cyclodextrin concentration of 5% w/v inwater.

[0040] The aripiprazole formulations of the invention are used to treatschizophrenia in human patients. The preferred dosage employed for theinjectable formulations of the invention will be a 2 ml injectioncontaining 7.5 mg aripiprazole/mL or a dose of 15 mg given three timesdaily at two hour intervals. The injectable formulation is preferablyadministered intramuscularly although subcutaneous and intravenousinjections are effective as well.

[0041] The following example represents a preferred embodiment of theinvention.

EXAMPLE

[0042] A clear colorless aripiprazole injectable solution (2 mgaripiprazole/mL, 4 mg/vial) essentially free of particulate matter byvisual inspection was prepared as follows.

[0043] A stainless steel batching vessel was charged with an appropriateamount of water for injection USP.

[0044] With continuous stirring, 78 g tartaric acid granular USP and1500 g sulfobutyl ether β-cyclodextrin (SBECD) was added to the batchingvessel and was dissolved in the water.

[0045] Aripiprazole 20 g was added to the batching vessel and stirringwas continued until the aripiprazole was dissolved.

[0046] Sodium hydroxide 1N was added to the above solution to adjust thepH thereof to about 4.3.

[0047] Additional water for injection USP was added to the abovesolution to adjust to the final batch size to 10 L with stirring.

[0048] The above solution was aseptically filtered through a 0.22 μMmembrane filter into a sterilized container 4 mg amounts of the abovesolution were aseptically filled into sterilized vials which were thenaseptically stoppered with sterilized stoppers to seal the vials.

What is claimed is:
 1. An inclusion complex of aripiprazole in asubstituted beta-cyclodextrin.
 2. The inclusion complex as defined inclaim 1 wherein the β-cyclodextrin is sulfobutyl ether β-cyclodextrin(SBECD) or hydroxypropyl β-cyclodextrin (HPBCD).
 3. The inclusioncomplex as defined in claim 2 wherein the cyclodextrin is SBECD.
 4. Apharmaceutical formulation comprising aripiprazole and a substitutedβ-cyclodextrin.
 5. The formulation as defined in claim 4 in the form ofan injectable formulation.
 6. The formulation as defined in claim 4wherein the substituted β-cyclodextrin is sulfobutyl etherβ-cyclodextrin (SBECD) or hydroxypropyl-β-cyclodextrin (HPBCD).
 7. Theformulation is defined in claim 4 comprising an aqueous injectableformulation having a pH within the range from about 3.5 to about
 5. 8.The formulation as defined in claim 7 including an acid buffer.
 9. Theformulation as defined in claim 8 wherein the acid buffer is tartaricacid or a salt thereof, citric acid or a salt thereof, hydrochloric acidor a salt thereof, acetic acid or a salt thereof, maleic acid or a saltthereof, malic acid or a salt thereof, sulfuric acid or a salt thereof,toluenesulfonic acid or a salt thereof, benzenesulfonic acid or a saltthereof, naphthalenesulfonic acid or a salt thereof, or ethanesulfonicacid or a salt thereof.
 10. The formulation as defined in claim 9further including a base to adjust pH of the aqueous formulation towithin the range from about 3.5 to about
 5. 11. The formulation asdefined in claim 8 wherein the substituted β-cyclodextrin is employed ina weight ratio to the aripiprazole within the range from about 10:1 toabout 100:1.
 12. The formulation as defined in claim 8 wherein the acidbuffer is employed in a weight ratio to the aripiprazole within therange from about 2:1 to about 10:1.
 13. The formulation as defined inclaim 5 wherein the aripiprazole is present in an amount to provide adosage from about 1 to 10 mg aripiprazole/mL.
 14. The formulation asdefined in claim 5 wherein the substituted β-cyclodextrin is SBECD andis present in a weight ratio to aripiprazole within the range from about20:1 to about 40:1.
 15. The formulation as defined in claim 5 whereinthe aripiprazole and the substituted-β-cyclodextrin are in the form ofan inclusion complex.
 16. The formulation as defined in claim 5 whereinthe formulation produces minimal irritation at the injection site. 17.An aqueous injectable formulation comprising aripiprazole, SBECD,tartaric acid, sodium hydroxide and water, said formulation having a pHwithin the range for about 4 to about 4.6.
 18. The formulation asdefined in claim 17 comprising aripiprazole in an amount to provide fromabout 1.5 to about 8 mg/mL of formulation, SBECD in an amount with therange from about 100 to about 200 mg/mL; tartaric acid in an amountwithin the range from about 7 to about 9 mg/mL sodium hydroxide qs toadjust pH within the range from about 4 to about 4.6; and water qs to 1mL.
 19. The formulation as defined in claim 18 wherein the aripiprazoleand the SBECD form an inclusion complex.
 20. The formulation as definedin claim 17 designed for intramuscular administration without causingunacceptable irritation.
 21. The formulation as defined in claim 15wherein the inclusion complex provides an amount of aripiprazole of atleast 2 mg aripiprazole/mL when the amount of aripiprazole provided bysaid complex, is measured at a substituted-β-cyclodextrin concentrationof 5% w/v in water.
 22. A method for administering injectablearipiprazole to a patient in need of treatment without causingunacceptable irritation at the site of injection, which comprisesadministering to a patient in need of treatment the formulation asdefined in claim
 17. 23. The method as defined in claim 22 wherein theformulation is administered intramuscularly.
 24. A method of treatingschizophrenia, which comprises administering to a patient in need oftreatment the formulation as defined in claim 5 without causing undueirritation at the site of administration.